Dermatological compositions and methods

ABSTRACT

Dermatological compositions (methods of making and using) that include one or more anesthetic agents and/or one or more anti-inflammatory agents and/or a combination of ammonium, sodium, and potassium salts, preferably of an alpha-hydroxy acid.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of Ser. No. 15/283,593,filed on Oct. 3, 2016, which is a continuation application of Ser. No.14/851,203, filed Sep. 11, 2015, now U.S. Pat. No. 9,456,970, which is acontinuation application of Ser. No. 13/198,928, filed on Aug. 5, 2011,now abandoned, which is a continuation application of Ser. No.12/479,524, filed on Jun. 5, 2009, now U.S. Pat. No. 8,013,017, which isa continuation application of Ser. No. 10/977,374, filed on Oct. 29,2004, now abandoned, which is a divisional application of Ser. No.10/159,562, filed on May 31, 2002, now abandoned, which claims thebenefit of U.S. Provisional Application Ser. No. 60/295,105 filed May31, 2001, each of which is incorporated by reference, in their entirety.

FIELD OF THE INVENTION

The invention relates to topical compositions that providedermatological benefit, such as for the treatment of inflammation,itching, pain relief, and/or other conditions associated with skindisorders.

BACKGROUND OF THE INVENTION

Severe dry skin disorders, known as ichthyosis, are often characterizedby cracks, flakes, scales, redness, etc. Less severe, but more common,moderate to mild dry skin disorders are often characterized by lesssevere fissures, chaps, cracks, flakes, redness, etc. Such disorders canalso include inflammation and be quite painful. Typically, suchdisorders are treated with topical oils, hydrating emollients,ointments, etc.

The topical use of alpha-hydroxy and beta-hydroxy acids,alpha-ketoacids, and esters thereof, is well known in the art to beeffective as a preventative as well as a therapeutic treatment of dryskin disorders. Treatment is generally effective at acid concentrationsof about 1% to about 20% by weight. Skin irritation caused by low pHlevels may be ameliorated by neutralizing the acids with a base, such asammonium hydroxide. See, for example, U.S. Pat. No. 4,105,783 (Yu etal.).

Further, it is believed that skin penetration by such compositions isenhanced using acid/base salts. See, for example, U.S. Pat. No.4,888,354 (Chang et al.). In addition, the topical compositions maycontain additional pharmaceutical and cosmetic additives, provided theydo not adversely affect the formulation, stability, and activity of theacids and/or esters. Such additives include, for example,antimicrobials, antibiotics, neoplastic agents, cardiac drugs,antihistamines, anesthetics, antipsychotics, etc. See, for example, U.S.Pat. No. 4,888,354 (Chang et al.), U.S. Pat. No. 5,420,106 (Parab), andU.S. Pat. No. 5,705,168 (Parab).

There is still a need for compositions (e.g., lotions and creams) thatcan be used to reduce conditions associated with dry skin and other skindisorders, such as inflammation, itching, and/or pain relief.

SUMMARY OF THE INVENTION

One aspect of the present invention combines dermatologically acceptablecompositions (i.e., dermatological or dermatologic compositions) withone or more anesthetic and/or anti-inflammatory agents, preferablysteroid anti-inflammatory agents. The compositions include at least oneacid, amide, ester, or salt of an alpha-hydroxy acid, a beta-hydroxyacid, an alpha-keto acid, or combinations thereof (preferably at leastone alpha-hydroxy acid, ester, amide, salt thereof, or combinationsthereof). More preferably, the compositions include a combination of atleast two salts, more preferably, at least one ammonium salt and atleast one metal ion salt (preferably sodium or potassium salt) forenhanced penetration of the composition. Preferably, certaincompositions include an anti-foaming agent.

A further aspect of the present invention is a composition including atleast one alpha hydroxy acid, at least one ammonium salt of an alphahydroxy acid, at least one potassium salt of an alpha hydroxy acid, andat least one sodium salt of an alpha hydroxy acid.

These compositions can also optionally include topical vehicles such asnon-ionic surfactants, thickeners, emollients, humectants, andpreservatives to provide preparations, such as lotions, creams, etc.,for dry skin having enhanced preventative and therapeutic attributes.

The present invention provides methods for treating a subject,preferably a mammal, and more preferably a human, such as reducinginflammation of the skin, reducing itching and/or pain of the skin, andtreating skin disorders that include contacting the skin with compoundscontaining any of the compositions of the present invention.

Another aspect of the present invention provides methods for preparingthe dermatological compositions that include combining at least oneacid, amide, ester, or salt of an alpha-hydroxy acid, beta-hydroxy acid,alpha-keto acid, or combinations thereof (preferably at least onealpha-hydroxy acid, ester, amide, salt thereof, or combinationsthereof), with one or more anesthetic agents and/or one or moreanti-inflammatory agents. Preferably, such methods also include addingone or more ammonium salts and/or one or more metal ion salts. Apreferred method of preparing certain dermatological compositions of thepresent invention includes providing an alpha-hydroxy acid andneutralizing at least a portion of it with ammonium hydroxide in anaqueous solution to provide a neutralized acid solution that preferablymay be combined with at least one anti-inflammatory agent and/or atleast one anesthetic agent.

A further method of preparing a dermatologic composition of the presentinvention includes combining at least one alpha-hydroxy acid,beta-hydroxy acid, or alpha-keto acid, or combinations thereof, with atleast one ammonium salt of an alpha-hydroxy acid, beta-hydroxy add, oralpha-keto acid, or combinations thereof, at least one sodium salt of analpha hydroxy acid, beta-hydroxy acid, or alpha-keto acid, orcombinations thereof, and at least one potassium salt of an alphahydroxy acid, beta-hydroxy acid, or alpha-keto acid, or combinationsthereof. Preferably, the method includes combining at least onealpha-hydroxy acid, beta-hydroxy acid, or alpha-keto acid, orcombinations thereof, with at least two of the above ammonium, sodium,and potassium salts.

High concentrations, such as from about 10% to about 30% by weight, ofalpha-hydroxy acids in a skin preparation, when neutralized to yield theammonium salts, have been found to develop an unpleasant odor andoccasionally may result in yellow coloration over time. Thus, thepresent invention also provides a method for preparing such compositionsusing activated charcoal for deodorizing. Compositions of the inventionmay be contacted with activated charcoal. Thereafter, the charcoal maybe separated from the composition. Compositions that may be contactedwith the activated charcoal may include compositions that have beenneutralized with ammonium hydroxide. Deodorizing is defined as removingor significantly reducing a fragrance by neutralization or adsorption.Odor-free is defined as a fragrance completely or substantiallyeliminated from a composition.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION

The invention concerns dermatological compositions that can be in theform of dermatologically acceptable lotions and creams, for example. Thecompositions of the present invention can be used to treat one or moreskin disorders, such as dry skin, ichthyosis, inflammation, andirritation. Certain preferred compositions can be used to reduce theamount of inflammation of the skin of a human. Certain other preferredcompositions can be used to reduce the amount of itching and/or pain ofthe skin of a human. Certain other preferred compositions include acombinations of salts that enhance skin penetration of the activeingredients of the compositions.

Acids, Amides, Esters, Salts

The dermatological compositions include at least one active ingredientselected from an acid, amide, ester, or salt. Preferably, such activeingredients are racemic mixtures and, preferably, are selected from thegroup of an alpha-hydroxy acid, a beta-hydroxy acid, an alpha-keto acid,an ester thereof, an amide thereof, a salt thereof, and combinationsthereof. More preferably, such active ingredients are selected from thegroup of an alpha-hydroxy acid, an amide thereof, an ester thereof, asalt thereof, and combinations thereof. Certain preferred embodimentsinclude a combination of at least one alpha-hydroxy acid and at leastone salt thereof. Preferably the salt is an ammonium salt, a metal ionsalt (e.g., a potassium salt or a sodium salt), or a combinationthereof. More preferably, a combination of such salts is used. Even morepreferably, at least two different salts are used. Most preferably, acombination of an ammonium salt, a potassium salt, and a sodium salt isused.

Examples of such acids, amides, esters, or salts include citric acid,glycolic acid, glucuronic acid, galacturonic acid, alpha-hydroxybutyricacid, alpha-hydroxyisobutyric acid, beta-hydroxybutyric acid, lacticacid, malic acid, mandelic acid, mucic acid, pyruvic acid, saccharicacid, tartaric acid, tartronic acid, maleic acid, beta-phenyllacticacid, beta-phenylpyruvic acid, glucuronolactone, gluconolactone, methylpyruvate, ethyl pyruvate, salts thereof, and combinations thereof.

A preferred set of such active ingredients includes the alpha-hydroxyacids. Alpha-hydroxy acids are aliphatic mono- and di-carboxylic acidsincluding, but not limited to, citric acid, glycolic acid, glucuronicacid, galacturonic acid, alpha-hydroxybutyric acid,alpha-hydroxyisobutyric acid, lactic acid, malic acid, mandelic acid,mucic acid, pyruvic acid, saccharic acid, tartaric acid, tartonic acid,and the like. Preferred alpha-hydroxy acids of the present invention arethose of the formula (I): R—CH(OH)—COOH, wherein R is an alkyl group ora hydrogen. Preferably, R is a C₁ to C₅ alkyl group including, forexample, methyl, ethyl, propyl, butyl, or pentyl as well as branchedgroups thereof. Preferred acids include lactic, glycolic, and malicacids. Most preferred is lactic acid.

Typically, the compositions include both an acid and a salt thereof, asfor example, an alpha-hydroxy acid and an ammonium salt thereof. Thealpha-hydroxy acids and a base, such as ammonium hydroxide, aretypically reacted in an aqueous solution to provide a neutralized acidsolution. Generally, at least a portion of the acid is neutralized.Thus, as used herein, a “neutralized” acid solution or combination ofacids in solution is defined as an acid solution in which at least aportion of the acid is neutralized to provide the salt of the acid oracids. The neutralized acid solution, formed when an acid is reactedwith an ammonium-containing base, such as ammonium hydroxide, can begenerally free of unreacted ammonia (herein “unreacted ammonia” refersto dissolved ammonium ions). This may occur when a stoichiometricallylesser amount of the base is added to the acid. A neutralized acidsolution, as defined herein, may also include solutions in whichunreacted ammonia is present.

The compositions preferably include one or more acids, amides, esters,or salts present in a total amount (e.g., acid plus salt) of at leastabout 1% by weight, more preferably at least about 5% by weight, andeven more preferably at least about 8% by weight, based on the totalweight of the composition (e.g., lotion, cream, etc.). Additionally, theone or more acids, amides, esters, or salts are present in thecompositions in a total amount no greater than about 50% by weight, morepreferably, no greater than about to about 40% by weight, and even morepreferably no greater than about 15%, based on the total weight of thecomposition. Typically, one or more acids, in the form of a free acid,in combination with one or more salts are present in the compositions.Preferably, the total amount of one or more free acids is at least about1% by weight, and more preferably, at least about 10% by weight, basedon the total weight of the composition. Preferably, the total amount ofone or more free acids is no greater than about 30% by weight, morepreferably, no greater than about 20% by weight, and most preferably nogreater than about 15% by weight, based on the total weight of thecomposition. Preferably, the total amount of one or more salts is atleast about 1% by weight, and more preferably, at least about 5% byweight, based on the total weight of the composition. Preferably, thetotal amount of one or more salts is no greater than about 40% byweight, and more preferably, no greater than about 30% by weight, basedon the total weight of the composition. The pH of the compositions ofthe present invention are preferably at least about 3, and morepreferably at least about 4.5, and preferably no greater than about 6,and more preferably no greater than about 5.5.

In certain preferred embodiments, the compositions include a combinationof one or more ammonium salts, one or more potassium salts, and one ormore sodium salts. Even more preferably, the compositions include acombination of 2 or more salts. In such compositions, preferably, thetotal amount of ammonium salts, if present, (preferably, of one or morealpha-hydroxy acids) is at least about 1% by weight, and morepreferably, at least about 5% by weight, based on the total weight ofthe composition. Preferably, the total amount of ammonium salts, ifpresent, (preferably, of one or more alpha-hydroxy acids) is no greaterthan about 40% by weight, and more preferably, no greater than about 30%by weight, based on the total weight of the composition. Mostpreferably, the ammonium salt is ammonium lactate and, if present, ispresent in an amount of, preferably at least about 10% and morepreferably at least about 15.9%, and preferably no greater than about29.6%, even more preferably no greater than about 15%, based on thetotal weight of the composition. In such compositions, preferably, thetotal amount of potassium salts, if present, (preferably, of one or morealpha-hydroxy acids) is at least about 1% by weight, and morepreferably, at least about 5% by weight, based on the total weight ofthe composition. Preferably, the total amount of potassium salts, ifpresent, (preferably, of one or more alpha-hydroxy acids) is no greaterthan about 30% by weight, and more preferably, no greater than about 20%by weight, based on the total weight of the composition. Mostpreferably, the potassium salt is potassium lactate and, if present, ispresent in an amount of at least about 3% and no greater than about 7%,based on the total weight of the composition. In such compositions,preferably, the total amount of sodium salts, if present, (preferably,of one or more alpha-hydroxy acids) is at least about 1% by weight, andmore preferably, at least about 5% by weight, based on the total weightof the composition. Preferably, the total amount of sodium salts, ifpresent, (preferably, of one or more alpha-hydroxy acids) is no greaterthan about 30% by weight, and more preferably, no greater than about 20%by weight, based on the total weight of the composition. Mostpreferably, the sodium salt is preferably sodium lactate and, ifpresent, is present in an amount of about 3% and no greater than about7%, based an the total weight of the composition.

Anesthetic Agents and/or Anti-Inflammatory Agents

Certain preferred compositions may additionally include one or moreanesthetic agents and/or anti-inflammatory agents to provide enhancedtherapeutic benefits to the skin preparation. Typically, ananti-inflammatory agent will reduce, and preferably, eliminate,inflammation of the skin of a subject when the composition is appliedtopically. Typically, an anesthetic agent will reduce, and preferably,eliminate, itching and/or pain of the skin of a subject when thecomposition is applied topically. Various combinations of such agentscan be used for desired effect.

Anesthetic agents that can be used in the present invention includetopical local anesthetics, such as anesthetics that can be usedtopically on the skin or can be injected as a local anesthetic. Examplesof such topical local anesthetic agents include, but are not limited to,pramoxine HCl, benzocaine, benzyl alcohol, dibucaine HCl, dyclonine HCl,lidocaine, tetracaine, and tetracaine HCl. Combinations of such agentscan be used. A preferred anesthetic agent is pramoxine HCl.

Preferably, the total amount of one or more anesthetic agents, ifpresent, is at least about 0.5% and more preferably at least about0.75%, based on the total weight of the composition. Preferably, thetotal amount of one or more anesthetic agent is no greater than about20%, and more preferably, no greater than about 5%, based on the totalweight of the composition.

Anti-inflammatory agents that can be used in the present inventioninclude steroids (i.e., corticosteroids). Examples of such agentsinclude, but are not limited to, hydrocortisone acetate, betamethasonedipropionate, amcinonide, betamethasone valerate, fluocinoloneacetonide, triamcinolone acetonide, clocortolone pivalate, anddexamethasone. Combinations of such agents can be used. A preferredsteroid for use in the present invention is hydrocortisone acetate.

Preferably, the total amount of one or more anti-inflammatory agents, ifpresent, is at least about 0.01%, and more preferably, at least about0.05% by weight, based on the total weight of the composition.Preferably, the total amount of one or more anti-inflammatory agent isno greater than about 2.5%, and more preferably, no greater than about1.5% by weight, based on the total weight of the composition.

Anti-Foaming Agents

Anti-foaming agents, or foam depressants, are optionally added to thecompositions of the present invention to prevent undesirable creamingupon application of the composition when rubbed into the skin.“Creaming” is understood by those skilled in the art to occur when acomposition rubbed into the skin forms a white layer on the skin beforepenetration. The more vigorously the composition is rubbed, the whiterthe composition becomes. It has been discovered that by adding ananti-foaming agent to a dermatological composition, creaming issubstantially eliminated. Although not caused exclusively by anestheticagents, creaming may occur when one or more topical anesthetic agents,particularly pramoxine HCl, is present in the composition. Pramoxine HClis a desirable anesthetic agent as compared with other anesthetics, suchas lidocaine and benzocaine, because many people have allergies to theseother anesthetics. Pramoxine HCl does not cause the same topicalsensitivity as compared to these other anesthetics, it is effective atminimal concentrations, and has a duration of action longer than that ofother anesthetics (see, for example, Fisher, A. F.; “The Safety ofPramoxine Hydrochloride When Used as a Topical (Surface) Anesthetic,”Cutis, 62:122-123 (1998); Fisher, A. A.; “Allergic Reactions to Topical(Surface) Anesthetics with Reference to the Safety of Tronothane,”Cutis, 25:584 (1980); and Schmidt, J. L., Blockus, L. E., Richards, R.K., “The Pharmacology of Pramoxine Hydrochloride: A New TopicalAnesthetic,” Anesth. Analg., 32:418 (1953)), but it does have theundesirable side-effect of causing creaming upon application to the skinwhen used in the compositions of the present invention. This problem issolved by including an anti-foaming agent in the compositions of thepresent invention.

Acceptable anti-foaming agents of the present invention includesilicone-based oils, preferably dimethylsiloxane polymers, and copolyolwaxes. Such dimethylsiloxane polymers are commercially available underthe trade designations DIMETHICONE 250, DIMETHICONE 350, DIMETHICONE450, CYCLOMETHICONE, and DIMETHICONE, all from Dow Corning, Midland,Mich. A particularly preferred anti-foaming agent is DIMETHICONE 350dimethylsiloxane polymer. Combinations of such agents can be used.Effective concentrations of DIMETHICONE 350 from Dow Corning, Midland,Mich., or other anti-foaming agents in the compositions of the presentinvention, if present, are at least about 0.25% by weight, morepreferably at least about 0.5% by weight, and most preferably at leastabout 0.8% by weight. Preferably, the compositions include no greaterthan about 3% by weight, more preferably no greater than about 2% byweight, and most preferably no greater than about to about 1.2% byweight.

Non-Ionic Surfactants

Non-ionic surfactants are present in preferred formulations to aid inproviding an emulsion of the composition. Selection of surfactant andconcentration of the surfactant will have a significant effect on theoverall “feel” of the composition. Also, a greater stability of thecomposition may be gained through the blending of multiple non-ionicsurfactants than may be achieved through the use of any singlesurfactant. Preferred non-ionic surfactants that may be used in thecompositions of the present invention include glyceryl stearate, PEG100-stearate, polyoxyl-20-cetostearyl ether, glyceryl monooleate,glyceryl palmitostearate, self-emulsifying wax, polyoxyl-20-stearate,polyoxyl-40-stearate, polyoxyl-60-stearate, polyoxyl-80-stearate,polyoxyl-20-oleate, polyoxyl-40-oleate, polyoxyl-60-oleate,polyoxyl-80-oleate, polyoxyl-20-palmitate, polyoxyl-40-palmitate,polyoxyl-60-palmitate, polyoxyl-80-palmitate, laureth-2, laureth-4,laureth-6, and laureth-8. More preferred non-ionic surfactants includeemulsifying wax, such as POLAWAX (available from Croda, Parsippany,N.J.), laureth-4, and polyoxyl-40-stearate. A most preferred non-ionicsurfactant is self-emulsifying wax.

Combinations of such agents can be used such as a combination isglyceryl stearate and PEG-100 stearate. A preferred non-ionic surfactantof the present invention includes a system of glyceryl stearate, PEG-100stearate, polyoxyl-40-stearate, and laureth-4. Glyceryl stearate andPEG-100 stearate are supplied pre-blended by Uniqema (formerly ICIAmericas, New Castle, Del.). Effective concentrations of the pre-blendedglyceryl stearate and PEG-100 stearate in the compositions of thepresent invention are at least about 2.0% by weight, and more preferablyat least about 2.75% by weight, based on the total weight of thecomposition. Preferably, compositions of the present invention containno greater than about 5.5% by weight, and more preferably no greaterthan about to about 5.25% by weight, based on the total weight of thecomposition. Polyoxyl-40-stearate is selected because the stearates tendto enhance composition stability in comparison to the oleates andpalmitates. Polyoxyl-40-stearate is available in cosmetic grade fromUniqema (New Castle, Del.). Effective concentrations ofpolyoxyl-40-stearate in the compositions of the present invention arepreferably at least about 0.5% by weight, and more preferably at leastabout 0.75% by weight, based on total weight of the composition.Preferably, effective concentrations of polyoxyl-40-stearate in thecompositions of the present invention are no greater than about 5% byweight, and more preferably no greater than about 1.25% by weight, basedon total weight of the composition. Effective concentrations oflaureth-4 in the compositions of the present invention are preferably atleast about 0.5% by weight, and more preferably at least about 1.25% byweight, based on total weight of the composition. Effectiveconcentrations of laureth-4 in the compositions of the present inventionare preferably no greater than about 3%, and more preferably no greaterthan about 1.75% by weight, based on total weight of the composition.Effective concentrations of emulsifying wax in preferred compositions ofthe present invention are preferably at least about 2% and preferably nogreater than about 10%, based on the total weight of the composition.

Thickeners

Although the non-ionic surfactants impart a certain amount of thickeningto the compositions of the present invention, it is difficult to findthe correct balance of surfactants and concentrations thereof that willimpart the desired stability to the composition. Therefore, thickeners,also known in the art as viscosity modifiers, are preferably used toadjust the composition to the desired consistency without affecting thestability imparted by the non-ionic surfactant system. Acceptablethickeners that may be used in the compositions of the present inventioninclude methyl cellulose, hydroxypropyl methyl cellulose, ethylcellulose, cetyl alcohol, cetostearyl alcohol, stearyl alcohol,magnesium aluminum silicate, xanthan gum, aluminum magnesium silicate,tribeneonite, kaolin, magnesium trisilicate, monemorillonite, saeonite,stearic acid, and talc. Combinations of such agents can be used.

A preferable thickener of the present invention includes a system ofmethyl cellulose, cetyl alcohol, and magnesium aluminum silicate.Magnesium aluminum silicate is particularly preferred element of thethickener system as it acts as both an emulsion stabilizer as well as aviscosity modifier. It also imparts to the composition a smooth, silky,slippery feel without affecting the stability of the compositioncontributed by the non-ionic surfactant system and does not interferewith the creaming prevention of the anti-foaming agent. Effectiveconcentrations of methyl cellulose in the compositions of the presentinvention are preferably at least about 0.0001% by weight, and morepreferably at least about 0.0005% by weight, based on total weight ofthe composition. Effective concentrations of methyl cellulose in thecompositions of the present invention are preferably no greater thanabout 1% by weight, and more preferably no greater than about 0.5% byweight, based on total weight of the composition. Effectiveconcentrations of cetyl alcohol in the compositions of the presentinvention are preferably at least about 0.2% by weight, and morepreferably at least about 0.5% by weight, based on total weight of thecomposition. Effective concentrations of cetyl alcohol in thecompositions of the present invention are preferably no greater thanabout 5% by weight, and more preferably no greater than about 3.25% byweight, based on total weight of the composition. Effectiveconcentrations of magnesium aluminum silicate in the compositions of thepresent invention are preferably at least about 0.5% by weight, morepreferably at least about 1% by weight, and most preferably at leastabout 1.25% by weight, based on total weight of the composition.Effective concentrations of magnesium aluminum silicate in thecompositions of the present invention are preferably no greater thanabout 10% by weight, more preferably no greater than about 5% by weight,and most preferably no greater than about 1.75% by weight, based ontotal weight of the composition.

An additional preferred thickener of compositions of the presentinvention includes stearic acid. In these preferred compositionsthickened using stearic acid, the stearic acid is preferably present inan amount of at least about 1% and no greater than about 5%, based ontotal weight of the composition.

Emollients and Humectants

Emollients and humectants soften the skin and stabilize and control themoisture content of a dermatological composition. Preferred emollientsthat may be used in the compositions of the present invention includeglycerin 99.5%, glycerin 95%, glycerin 85%, cetyl alcohol, light mineraloil, medium mineral oil, and heavy mineral oil. Preferred humectantsthat may be used in the compositions of the present invention includeglycerin 99.5%, glycerin 95%, glycerin 85%, propylene glycol, andbutylene glycol. Combinations of such agents can be used.

More preferable emollients and humectants of the present inventioninclude glycerin 99.5%, propylene glycol, and light mineral oil.Glycerin 99.5% and propylene glycol, when used together, typically actsynergistically to aid in stabilizing compositions of the presentinvention. Further, propylene glycol enhances penetration of the skin bycompositions at concentrations of 5% by weight or more, based on totalweight of the composition. Conversely, butylene glycol used alone is nota penetration enhancer, but does work synergistically with glycerin99.5% to enhance penetration. Effective concentrations of glycerin 99.5%in the compositions of the present invention are preferably at leastabout 1% by weight, more preferably at least about 3% by weight, andeven more preferably at least about 3.75% by weight, based on totalweight of the composition. Effective concentrations of glycerin 99.5% inthe compositions of the present invention are preferably no greater thanabout 10% by weight, more preferably no greater than about 6% by weight,and even more preferably no greater than about 4.25% by weight, based ontotal weight of the composition. Effective concentrations of propyleneglycol in the compositions of the present invention are preferably atleast about 1% by weight, and more preferably at least about 3% byweight, based on total weight of the composition. Effectiveconcentrations of propylene glycol in the compositions of the presentinvention are preferably no greater than about 15% by weight, and morepreferably no greater than about 10% by weight, based on total weight ofthe composition.

Light mineral oil is preferable as an emollient as it imparts less of agreasy feel to the composition, giving it a lighter feel than do theheavier oils. Effective concentrations of light mineral oil in thecompositions of the present invention are preferably at least about 1%by weight, more preferably at least about 3% by weight, even morepreferably at least about 4% by weight, and most preferably at leastabout 5% by weight, based on total weight of the composition. Effectiveconcentrations of light mineral oil in the compositions of the presentinvention are preferably no greater than about 20% by weight, morepreferably no greater than about 15% by weight, and most preferably nogreater than about 12% by weight, based on total weight of thecomposition.

Preservatives

Preservatives prolong the useful life of the composition by killingbacteria, yeasts, and molds which may impair the effectiveness of thecompositions of the present invention. Preferable preservatives that maybe used in the compositions of the present invention includemethylparaben, ethylparaben, propylparaben, propylparaben potassiumsalt, propylparaben sodium salt, and butylparaben. Combinations of suchagents can be used. More preferable preservatives of the presentinvention include methylparaben and propylparaben. Methyl andpropylparaben attack water-bourne microbes, and when used together,their effectiveness is greater than each used alone. Effectiveconcentrations of methylparaben in the compositions of the presentinvention are preferably at least about 0.02% by weight, and morepreferably at least about 0.1% by weight, based on total weight of thecomposition. Effective concentrations of methylparaben in thecompositions of the present invention are preferably no greater thanabout 1% by weight, more preferably no more than about 0.3% by weight,and even more preferably no greater than about 0.2% by weight, based ontotal weight of the composition. Effective concentrations ofpropylparaben in the compositions of the present invention arepreferably at least about 0.01% by weight, more preferably at leastabout 0.025% by weight, and even more preferably at least about 0.1%,based on total weight of the composition. Effective concentrations ofpropylparaben in the compositions of the present invention arepreferably no greater than about 1% by weight, more preferably nogreater than about 0.6% by weight, and even more preferably no greaterthan about 0.075% by weight, based on total weight of the composition.

Fragrance

If desired, a component may be added to the composition to impart afragrance. Fragrances may be used to add a pleasing scent to a generallyunscented composition or, alternatively, may be used to assist inconcealing the odor of a composition having a strong and/or unpleasantscent. Fragrance components, if included in a preferred composition, arepreferably present in the compositions in an amount of no greater thanabout 1% by weight, based on the total weight of the composition.

Water, preferably purified water, is typically and preferably used inthe compositions of the invention. Water may be used in any amountrequired to prepare the compositions of the invention, but is typicallypresent in an amount of at least about 30% and typically no greater thanabout 60% by weight, based on the total weight of the composition.

Methods of Preparation

An acid/acid salt solution is made by mixing a selected alpha-hydroxy,beta-hydroxy, alpha-keto acid, an ester, amide, or salt thereof, anammonium salt, a metal ion salt, or a combination of any of the above,with purified water or by neutralizing an acid with a stoichiometricallylesser amount of base, such as ammonium hydroxide, to form the“neutralized” acid/acid salt solution. Alternatively, a commerciallyavailable salt, such as an ammonium lactate solution (available fromPURAC America, Lincolnshire, Ill., or Pfanstiehl Labs, Inc., Waukegan,Ill.) may be combined with an acid to form an acid/acid salt solution.

A Gum Phase composition is preferably prepared by mixing a thickenerand, optionally, fillers, into hot, purified water, mixing until uniformat a temperature of about 80° C. to about 85° C. A Water Phasecomposition is preferably prepared using hot purified water, optionallyincluding emulsifiers, humectants, lubricants, thickeners, andantimicrobial agents. The Gum Phase is typically transferred to theWater Phase and mixed, maintaining a temperature of about 80° C. toabout 85° C. An Oil Phase composition is preferably prepared by mixingmineral oil with, optionally, one or more of a surfactant, a lubricant,an emulsifier, a foam stabilizer and an emollient. The Oil Phase istypically heated to about 80° C. to about 85° C. An Active Phasecomposition is preferably prepared by dissolving and mixing one or moreof an anesthetic agent and/or an anti-inflammatory agent with purifiedwater.

The Oil Phase is typically added to the Water Phase, mixed, and cooled.To this, preferably, the acid/acid salt composition is added, withmixing, and to this the Active Phase is preferably added, with continuedmixing. The pH of the resulting composition is adjusted to the desiredlevel using either base or acid, and any desired optional agents, suchas anesthetics or anti-inflammatory agents, are then added to thecomposition, as disclosed in the Examples.

Deodorized Compositions

One of the problems associated with neutralizing the alpha-hydroxy acidwith ammonium hydroxide is that in the reaction product, free orunreacted ammonia is present. In dermatological preparations, such aslotions and creams, that contain low concentrations of reactive product,the unreacted ammonia is not often noticeable nor objectionable. Athigher concentrations of the reactive product, however, such asneutralized alpha-hydroxy acid greater than 10% by weight, unreactedammonia from the dermatological preparations can give off a strong,unpleasant ammonia odor. Currently available products having a highpercentage of unreacted ammonia employ fragrances to mask the unpleasantodor of ammonia. A disadvantage to the use of fragrances to mask theodor is that many patients who require treatment with highconcentrations of alpha-hydroxy acids are at the same time allergic tosuch fragrances and may experience irritation and stinging. Often thediseased skin becomes abraded or broken. Use of fragrances in productsapplied to the skin may result in unpleasant side effects. A furtherproblem associated with high concentrations of the neutralizedalpha-hydroxy acids is that the preparations occasionally develop ayellow coloration over time.

In order to prepare a deodorized composition of the present invention,the alpha-hydroxy acid is combined with ammonium hydroxide, to provide aneutralized acid solution containing unreacted ammonia. Before combiningthe neutralized acid solution, containing unreacted ammonia, with theselected anesthetic and/or anti-inflammatory agents or otheringredients, the reaction product is contacted with activated carbon.The activated carbon purifies, decolorizes, and removes odor from thecomposition by absorbing unreacted ammonia, and other impurities thatmay be present in the composition, onto the surface of the carbonparticles. The deactivated carbon has an extremely large surface areaper unit weight making it an efficient absorptive material. The‘activation’ of carbon in its manufacture produces many pores within thecarbon particles. It is the vast area of the walls within these poresthat accounts for most of the total surface area of the carbon.

Activated carbon adsorption is a time-release phenomenon that takesplace in three steps. Initially, impurities in solution contact theexternal surface of a carbon particle as the liquid passes through thecarbon bed. Secondly, impurities diffuse into the pores of the carbonparticle. Finally, impurities are attracted to the pore wall and held byelectrostatic (physical) or chemical forces. The adsorption methodrequired to deodorize the compositions of the present invention isdependent on contact time with the carbon, unreacted ammoniaconcentration, impurity concentration, and adsorption affinity.

Deodorizing methods of the present invention preferably include passingthe neutralized solution, containing unreacted ammonia, through anactivated carbon cartridge to provide a deodorized filtrate. Thefiltrate is then typically combined with one or more anesthetic agentsdescribed above and/or one or more anti-inflammatory agents describedabove, providing a composition for use in dermatological formulations.

Methods of the present invention alternatively include forming a slurryof activated carbon particles and neutralized acid solution containingunreacted ammonia, which is then filtered to provide the deodorizedcomposition of the present invention. A preferred method for large scalecommercial preparation involves adding activated carbon to theneutralized solution to form a slurry which is stirred prior tofiltering. The amount of activated carbon necessary in the method of thepresent invention may vary from about 30% to about 75% by weight of thetotal aqueous solution of the neutralized alpha-hydroxy acid. The slurryof the activated carbon and neutralized acid is stirred at ambienttemperatures for about 15 minutes to about 2 hours. Following thistreatment, the carbon is filtered off and the deodorized filtrate iscombined with the selected anesthetic and/or anti-inflammatory agents.

Optional Additives

The resulting composition is used to prepare dermatological formulationsin the form of, for example, creams and lotions, in accordance with wellknown procedures. Such formulations are well known to those of skill inthe art. Examples of additives, as indicated above, which may be used informulating creams include, but are not limited to, petrolatum,non-ionic surfactants, mineral oil, long-chain alcohols, and fattyacids. Examples of additives used in formulating lotions include, butare not limited to, propylene glycol and non-ionic surfactants.

EXAMPLES

Objects and advantages of this invention are further illustrated by thefollowing examples, but the particular materials and amounts thereofrecited in these examples, as well as other conditions and details,should not be construed to unduly limit this invention.

Examples 1-4

Preparation of Compositions Containing Anti-Inflammatory and/orAnesthetic Agents

Four preferred formulations, Formulations A-D, of a moisturizing creamare listed in Table 1. These compositions were made using the followingprocedure:

Ammonium Lactate Solution

A 50-70% ammonium lactate solution was purchased from Pfanstiehl Labs(Waukegan, Ill.) or PURAC America (Lincolnshire, Ill.).

Gum Phase Preparation

A portion of the purified water was measured into a jacketed kettle. Thewater was haled to about 80° C. to about 85° C. and mixed. Withcontinued mixing, the magnesium aluminum silicate, NF (Vanderbilt,Norwalk Conn.) and methyl cellulose, USP, (Dow Chemical, Midland, Mich.)were added to the water. The Gum Phase was mixed for at least 45minutes, until uniform, while maintaining a temperature of about 80° C.to about 85° C.

Water Phase Preparation

To a jacketed compounding kettle the following ingredients were addedusing a transfer pump: hot purified water, USP, and glycerin, 99.5%, USP(Dow Chemical, Midland, Mich.). The transfer pump was rinsed withadditional purified water. The Water Phase was mixed. The Gum Phase wastransferred to the Water Phase using a transfer pump fitted with a 60mesh screen. The Gum Phase kettle was rinsed with additional hotpurified water, USP. The Water Phase and Gum Phase mixture was mixed forat least about 15 minutes while adjusting the temperature to about 80°C. to about 85° C. The methylparaben (Napp Technologies, Saddlebrook,Ill.) was added. The Water/Gum Phase was mixed for about 20 minutes toabout 35 minutes while maintaining a temperature of about 80° C. toabout 85° C.

Oil Phase Preparation

To a jacketed compounding kettle the following ingredients were added:

light mineral oil, NF (Penreco, Karns City, Pa.), propylene glycol, USP(Dow Chemical, Midland, Mich.), laureth-4 (Uniqema, New Castle, Del.), aglyceryl stearate and PEG-100 stearate blend (Uniqema, New Castle,Del.), polyoxyl-40-stearate, NF (Uniqema, New Castle, Del.), cetylalcohol, NF (Croda, Parsippany, N.J.), DIMETHICONE 350 (Dow Corning,Midland, Mich.), and propylparaben, NF (Napp Technologies, Saddlebrook,Ill.). The ingredients were mixed and heated to about 80° C. to about85° C.

Active Phase Preparation

Into a compounding kettle purified water, USP, was weighed out. Thepramoxine HCl, USP (Abbott Labs, Waukegan, Ill.) was added to the water.The solution was mixed until the pramoxine HCl was dissolved.

Emulsion Phase

When the temperatures of the water and oil phases were about 80° C. toabout 85° C. the oil phase was added to the water phase using a transferpump. The emulsion was mixed for at least about 30 minutes. The emulsionwas cooled with ambient water while mixing until the batch temperaturereached was about 45° C. to about 50° C. When this temperature wasreached, the ammonium lactate solution was added using a transfer pump.The pump was rinsed with purified water, USP. Active vacuum was appliedto the emulsion at about 12 inches Hg. to about 14 inches Hg. Coolingand mixing continued until the emulsion reached about 39° C. to about41° C. The vacuum was released and the active phase was added using atransfer pump with continued mixing. The transfer pump was rinsed withadditional purified water, USP. Active vacuum was applied at about 12inches Hg to about 14 inches Hg. (about 0.40 atm. to about 0.47 atm.)while cooling continued until a product temperature of about 37° C. wasreached. When the batch reached about 37° C., vacuum was released, thecooling water drained from kettle jacket and steam applied to jacket forabout 60 seconds to about 90 seconds to relieve emulsion plating on thekettle walls. The vacuum was reapplied at about 12 inches Hg to about 14inches Hg. (about 0.40 atm. to about 0.47 atm). Ambient cooling waterwas reapplied to the jacket and the batch was cooled to about 35° C.

pH Adjustment

A sample of the emulsion was removed. The pH was measured. If it waswithin about 4.5 to about 5.5, the batch was complete. If the pH was notwithin this range, either strong ammonia solution was added to increasethe pH or lactic acid, USP was added to decrease the pH. Mixing wascontinued while the pH was adjusted.

TABLE 1 Percentages by weight Ingredient Formula A Formula B Formula CFormula D Purified Water, USP 45.80 45.80 44.80 45.9 Methylparaben, NF0.15 0.15 0.15 0.15 Glycerin, 99%, USP 4.00 4.00 4.00 4.00 Methylcellulose, NF 0.001 0.001 0.001 0.001 Magnesium Aluminum 1.5 1.50 1.501.50 Silicate, NF Light Mineral Oil, NF 10 10.00 10.00 10.00 PropyleneGlycol, USP 5.00 5.00 5.00 5.00 Glyceryl Stearate (and) 5.00 5.00 5.005.00 PEG-100 Stearate (pre-blended) Polyoxyl-40-stearate, NF 1.00 1.001.00 1.00 Cetyl Alcohol, NF 1.00 1.00 1.00 3.00 Propylparaben, NF 0.050.05 0.05 0.05 Laureth-4 1.5 1.50 1.50 1.50 DIMETHICONE 350 0 0 0 1.00Pramoxine HCl, USP 0 1.00 1.00 1.00 Hydrocortisone Acetate, 1.00 0 1.000 USP Ammonium Lactate, 24.00 24.00 24.00 21.90 60%¹ Lactic Acid 12.1012.10 12.10 12.00 Concentration ¹Actual amount varies depending on thepotency of ammonium lactate solution to be equivalent to 12% lacticacid. Ammonium Lactate is a 50%-70% solution, Formulas A through C,calculation is based on 60%. Nominal percentage is shown for Formula D.

Examples 4-6 Multiple Counter Ion Cream Formulations

Three preferred formulations, Formulations E-G, of moisturizing creamswhich, according to the present invention, incorporate ammonium andmetal ion salts along with the acid/acid salt composition, are listed inTable 2. These compositions were made using the following procedure:

Hot Water/Active Phase

Water, methylparaben (Napp Technologies, Saddlebrook, Ill.), glycerin99.5% (Dow Chemical, Midland, Mich.), and propylene glycol (DowChemical, Midland, Mich.) were combined and heated with mixing to about70° C. to about 75° C. in a covered vessel. Active ingredients, such aspramoxine HCl (Abbott Labs, Waukegan, Ill.) or hydrocortisone acetate(Ceres Chemical, White Plains, N.Y.) were optionally added to the hotwater phase to provide a hot water/active phase.

Oil Phase

Mineral oil (Penreco, Karns City, Pa.), stearic acid (Croda, Parsippany,N.J.), and self-emulsifying wax (POLAWAX, Croda, Parsippany, N.J.) wascombined and heated with stirring to about 68° C. to about 72° C.

Emulsion Phase

The hot water/active phase was preferably added to the oil phase wheneach phase was within the specified temperature range to provide anemulsion. The emulsion was cooled until it reached about 40° C. to about45° C. The lactate solutions were preferably added and mixing continueduntil smooth and well blended.

TABLE 2 Percentages by weight Ingredient Formula E Formula F Formula GWater 52.45 45.05 45.05 Methylparaben, USP 0.15 0.15 0.15 Glycerin99.5%, USP 4.0 4.0 4.0 Propylene Glycol 5.0 5.0 5.0 Light Mineral Oil10.0 10.0 10.0 Stearic Acid 5.0 8.0 8.0 Self-emulsifying wax (POLAWAX)7.0 8.0 8 Ammonium Lactate, 70% 5.2 5.8 5.8 Sodium Lactate, 60% 5.6 6.56.5 Potassium Lactate, 60% 5.6 6.5 6.5 Pramoxine HCl, USP 0 1.0 0Hydrocortisone Acetate, USP 0 0 1.0 TOTAL 100 100 100 Actual Lactic AcidConcentration 7.6 8.8 8.8

Examples 7 and 8 Formulation for a Deodorized Lotion and Cream

Percentage by Weight Raw Material Lotion Cream Purified water, USP49.199 48.799 Ammonium lactate solution 22.00* 22.00* Light mineral oil,NF 10.0 10.00 Glyceryl stearate (and) PEG-100 stearate 3.00 5.00Propylene glycol, USP 5.00 5.00 Glycerin, USP 99.5 4.00 4.00 Laureth-41.50 1.50 Magnesium aluminum silicate, NF 1.50 1.50Polyoxyl-40-stearate, NF 1.00 1.00 Cetyl alcohol, NF 0.60 1.00Methylparaben, NF 0.15 0.15 Propylparaben, NF 0.05 0.05 Methylcellulose0.001 0.001 *Deodorized as described below.

Procedure

All raw materials were weighed and the mixer was prepared.

Water Phase

The purified water was heated to about 90° C. to about 95° C. At amoderate mixing speed, the magnesium aluminum silicate (Vanderbilt,Norwalk, Conn.) was added. With continued moderate mixing, themethylcellulose (Dow Chemical, Midland, Mich.) and glycerin (DowChemical, Midland, Mich.) were added, maintaining the temperature ofabout 90° C. to about 95° C. Moderate mixing was continued until thewater phase was uniform, at least about 2 minutes, maintaining atemperature of about 90° C. to about 95° C. To this composition themethylparaben (Napp Technologies, Saddlebrook, Ill.) was added, withcontinued moderate mixing. Mixing was maintained for at least about 10minutes, until the composition was smooth and homogeneous, whileadjusting the temperature to about 80° C. to about 85° C.

Oil Phase (in a Separate Container)

In a separate container, the light mineral oil (Penreco, Karns City,Pa.), the glyceryl stearate and PEG-100 stearate mixture (Uniqema, NewCastle, Del.), propylene glycol (Dow Chemical, Midland, Mich.),polyoxyl-40-stearate (Uniqema, New Castle, Del.), cetyl alcohol (Croda,Parsippany, N.J.), propylparaben (Napp Technologies, Saddlebrook, Ill.),and laureth-4 (Uniqema New Castole, Del.) were combined and mixed at lowspeed, 150 rpm, while they were heated to about 80° C. to about 85° C.until the ingredients were completely melted and the composition wasuniform.

Emulsion Phase

When the temperatures of both the water and oil phases were at about 80°C. to about 85° C., the oil phase was added to the water phase whilemixing at about 270 revolutions per minute (rpm) for about 15 minutes.Mixing was continued at about 102 to about 135 rpm for at least about 45minutes. The composition was then cooled while mixing at about 141 toabout 179 rpm until the temperature of the composition reached 40° C. orbelow. The ammonium lactate (Pfanstiehl Labs, Waukegan, Ill., or PURACAmerica, Lincolnshire, Ill.) was then added, and the composition wascooled, with mixing at about 140 to about 165 rpm, until the compositionwas smooth and uniform, with a final temperature of about 33° C.

Preparation of a Deodorized Composition

In addition to preparing a neutralized acid solution from alpha-hydroxyacid and ammonium hydroxide, such neutralized preparations may bepurchased. Nondeodorized ammonium lactate can be purchased from severalsources, for example, from PURAC America (Lincolnshire, Ill.). Theproduct is a liquid containing between 58%-64% lactate and 8%-12%ammonium. Lactic acid is produced by fermentation from sugars and isneutralized with ammonium hydroxide to produce ammonium lactate. Themethod for deodorizing ammonium lactate involves producing a slurry ofammonium lactate with about 30 weight percent per volume of totalsolution of activated charcoal and mixing for about 30 minutes. Theslurry is then filtered to remove the activated charcoal. The resultingsolution of ammonium lactate is deodorized. An additional benefit tofiltering with activated charcoal is that any impurities that may causean off color are also removed, leaving a clear solution. The deodorizedammonium lactate is then combined with one or more anesthetic and/oranti-inflammatory agents.

Deodorizing Using an Activated Carbon Cartridge

Using an activated carbon cartridge, one liter of ammonium lactate ispassed through the cartridge. The resulting solution has no odor orcolor.

Deodorizing Using a Slurry

Five hundred kg of activated carbon/charcoal is added to a stainlesssteel vessel containing 1000 liters of ammonium lactate. The slurry isstirred for a minimum of 30 minutes, then is filtered. The resultingodorless and colorless filtrate is used to prepare creams and lotions.

The complete disclosures of the patents, patent documents, andpublications cited herein are incorporated by reference in theirentirety as if each were individually incorporated. Variousmodifications and alterations to this invention will become apparent tothose skilled in the art without departing from the scope and spirit ofthis invention. It should be understood that this invention is notintended to be unduly limited by the illustrative embodiments andexamples set forth herein and that such examples and embodiments arepresented by way of example only with the scope of the inventionintended to be limited only by the claims set forth herein as follows.

What is claimed is:
 1. A dermatological composition comprising: about 8weight percent to about 40 weight percent of deodorized ammoniumlactate; about 1 weight percent to about 20 weight percent of mineraloil; about 0.5 weight percent to about 3 weight percent ofdimethylsiloxane polymers. a nonionic surfactant; a preservative; about1 weight percent to about 10 weight percent of glycerin; about 0.0001weight percent to about 10 weight percent of xanthan gum; stearylalcohol; about 30% and typically no greater than about 60% by weight ofwater; wherein the composition has a pH of about 4.5 to about 5.5. 2.The dermatological composition of claim 1 wherein: the deodorizedammonium lactate is present in the composition in an amount of about19.7 weight percent; the mineral oil is present in the composition in anamount of about 10 weight percent; the dimethylsiloxane polymers arepresent in the composition in an amount of about 2 weight percent; theglycerin is present in the composition in an amount of about 4 weightpercent; the xanthan gum is present in the composition in an amount ofabout 0.2 weight percent; and the nonionic surfactant comprises glycerylstearate.
 3. A dermatological composition comprising: about 10 weightpercent to about 15 weight percent of ammonium lactate; about 3 weightpercent to about 7 weight percent of sodium lactate; about 3 weightpercent to about 7 weight percent of potassium lactate; about 1 weightpercent to about 20 weight percent of mineral oil; about 0.5 weightpercent to about 3 weight percent of dimethylsiloxane polymers. anonionic surfactant; a preservative; petrolatum; about 1 weight percentto about 10 weight percent of glycerin; about 0.0001 weight percent toabout 10 weight percent of xanthan gum; stearyl alcohol; about 30% andtypically no greater than about 60% by weight of water; wherein thecomposition has a pH of about 4.5 to about 5.5.
 4. The dermatologicalcomposition of claim 3 wherein: the ammonium lactate is present in thecomposition in an amount of about 10.5 weight percent; the sodiumlactate is present in the composition in an amount of about 4.2 weightpercent; the potassium lactate is present in the composition in anamount of about 4.2 weight percent; the mineral oil is present in thecomposition in an amount of about 4 weight percent; the dimethylsiloxanepolymers are present in the composition in an amount of about 2 weightpercent; the glycerin is present in the composition in an amount ofabout 5 weight percent; the xanthan gum is present in the composition inan amount of about 0.3 weight percent; and the nonionic surfactantcomprises glyceryl stearate.
 5. A method of treating skin of a subject,the method comprising contacting the subject's skin with a dermatologiccomposition of claim
 1. 6. A method of treating skin of a subject, themethod comprising contacting the subject's skin with a dermatologiccomposition of claim
 2. 7. A method of treating skin of a subject, themethod comprising contacting the subject's skin with a dermatologiccomposition of claim
 3. 8. A method of treating skin of a subject, themethod comprising contacting the subject's skin with a dermatologiccomposition of claim 4.